Tricyclic azaindolizine derivatives having an sPLA2-inhibitory activities
1. Technical Field
The present invention relates to tricyclic azaindolizine derivatives effective for inhibiting sPLA2-mediated fatty acid release.
2. Background Art
sPLA2 (secretory phospholipase A2) is an enzyme that hydrolyzes membrane phospholipids and has been considered to be a rate-determining enzyme that governs the so-called arachidonate cascade where arachidonic acid, the hydrolysis product, is the starting material. Moreover, lysophospholipids that are produced as by-products in the hydrolysis of phospholipids have been known as important mediators in cardiovascular diseases. Accordingly, in order to normalize excess functions of the arachidonate cascade and the lysophospholipids, it is important to develop compounds which inhibit the liberation of sPLA2-mediated fatty acids (for example, arachidonic acid), namely, compounds which inhibit the activity or production of sPLA2. Such compounds are useful for general treatment of symptoms, which are induced and/or sustained by an excess formation of sPLA2, such as septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, cardiac infarction, and so on. The participation of sPLA2 is considered to be extremely wide and, besides, its action is potent.
As examples of sPLA2 inhibitors are described indole derivatives [EP-620214 (JP Laid-Open No. 010838/95), EP-620215 (JP Laid-Open No. 025850/95), EP-675110 (JP Laid-Open No. 285933/95), and WO 96/03376], indene derivatives (WO 96/03120), indolizine derivatives (WO 96/03383), naphtyl derivatives (WO 97/21664 and WO 9721716), and carbazole derivatives (WO 98/18464), pyrazine derivatives (WO99/51605), and the like.
The object of the present invention is to provide tricyclic azaindolizine derivatives having sPLA2-inhibitory activities and being useful for treatment of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, and cardiac infarction.
The present invention relates to I) a compound represented by the formula (I): 
wherein E is N or Cxe2x80x94R4;
when E is N, G is Cxe2x80x94R25, or when E is Cxe2x80x94R4, G is N;
R1 is a group selected from (a) C1 to C20 alkyl, C1 to C20 alkenyl, C1 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, or (c) xe2x80x94(L1)xe2x80x94R5 wherein L1 is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfur atom(s), and R5 is a group selected from the groups (a) and (b);
one of R5 and R4 is xe2x80x94(L2)-(acidic group) wherein L2 is an acid linker having an acid linker length of 1 to 6 and the other is a hydrogen atom;
A ring is a group represented by the formula: 
wherein R2 is CONH2, CONHNH2 or CSNH2;
R18, R19, R20, R21, R22, R23, R26, and R27 are each independently a hydrogen atom, or lower alkyl;
R24 and R25 are each independently a hydrogen atom, C1 to C6 alkyl, aryl, a halogen or aralkyl;
its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
In more detail, the present invention relates to II)-XVI).
II) A compound represented by the formula (II): 
wherein R24 and A ring are as defined above;
J is N or Cxe2x80x94R8; when J is N, G is Cxe2x80x94R25 (wherein R25 is as defined above), or when
J is Cxe2x80x94R8, G is N;
R6 is xe2x80x94(CH2)mxe2x80x94R9 wherein m is an integer from 1 to 6, and R5 is (d) a group represented by the formula: 
wherein a, c, e, n, q, t and v are each independently 0, 1, or 2; R10 and R11 are each independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, optionally substituted phenyl, and C1 to C10 haloalkyl; xcex1 is an oxygen atom or a sulfur atom; xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; xcex3 is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are each independently an integer from 0 to 5; r is an integer from 0 to 7; and u is an integer from 0 to 4, or R9 is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, phenyl, and a halogen;
one of R7 and R5 is hydrogen and the other is xe2x80x94(L3)xe2x80x94R12 wherein L3 is represented by the formula: 
wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R15)xe2x80x94, or xe2x80x94Sxe2x80x94; R13 and R14 are each independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or a halogen, and R15 is a hydrogen atom or C1 to C6 alkyl; and
R12 is represented by the formula: 
wherein R16 is a hydrogen atom, a metal, or C1 to C10 alkyl; R17 is independently a hydrogen atom or C1 to C10 alkyl; h is an integer from 1 to 8; its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may substitute at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
III) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in I) or II), wherein R1 and R6 are represented by the formula: 
wherein R10, R11, b, d, f, p, r, u, w, xcex1, xcex2, and xcex3 are as defined above.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may substitute at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
IV) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in any one of I) to III), wherein R11 and R6 are represented by the formula: 
wherein R10, R11, d, p, u, and w are as defined above.
When the above p, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another.
V) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in any one of I) to IV), wherein R3 and R7 are xe2x80x94Oxe2x80x94(CH2)mxe2x80x94COOH (m is as defined above) or xe2x80x94Oxe2x80x94CH(xe2x80x94R30)xe2x80x94COOH (R30 is a hydrogen atom or C1-C3 alkyl).
VI) A compound represented by the formula (III): 
wherein G, J, R10, R30, A ring, and m are as defined above; B ring is a benzene ring or a cyclohexane ring; R38 is hydrogen atom or C1-C3 alkyl, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
VII) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in any one of I) to VI), wherein said R2 is xe2x80x94CONH2.
VIII) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in any one of I) to VII), wherein R18, R19, R20, R21, R22, and R23 are hydrogen atoms.
IX) A pharmaceutical composition containing a compound as claimed in any one of I) to VIII) as an active ingredient.
X) A pharmaceutical composition as claimed in IX), which is for inhibiting sPLA2.
XI) A pharmaceutical composition as claimed in IX), which is for inhibiting type I sPLA2.
XII) A pharmaceutical composition as claimed in IX), which is for inhibiting type II sPLA2.
XIII) A pharmaceutical composition as claimed in IX), which is for inhibiting type V sPLA2.
XIV) A pharmaceutical composition as claimed in IX), which is for inhibiting type X sPLA2.
XV) Use of a compound of any one of I) to VIII) for preparation of a pharmaceutical composition for treating diseases caused by sPLA2.
XVI) A method for treating a mammal, including a human, to alleviate the pathological effects of diseases caused by sPLA2, which comprises administration to said mammal of a compound described in any one of I) to VIII) in a pharmaceutically effective amount.
In the present specification, the term xe2x80x9calkylxe2x80x9d employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms. An example of the alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanyl and the like.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms in the present specification means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one double bond. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like.
The term xe2x80x9calkynylxe2x80x9d used in the present specification means a straight or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond(s). An example of the alkynyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, 8-nonynyl and the like.
The term xe2x80x9ccarbocyclic groupxe2x80x9d used in the present specification means a group derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered, preferably 5 to 10 membered, and more preferably 5 to 7 membered organic nucleus whose ring forming atoms (other than hydrogen atoms) are solely carbon atoms. A group containing two to three of the carbocyclic group is also included in the above stated group. An example of typical carbocyclic groups includes (f) cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooptenyl); cycloalkenyl (such as cyclobutylenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl); phenyl, naphthyl, norbornyl, bicycloheptadienyl, indenyl, stilbenyl, terphenylyl, phenylcyclohexenyl, acenaphthyl, anthoryl, biphenylyl, bibenzylyl, and a phenylalkylphenyl derivative represented by the formula (IV): 
wherein x is an integer from 1 to 8.
The term xe2x80x9cheterocyclic groupxe2x80x9d used in the present specification means a group derived from monocyclic or polycyclic, saturated or unsaturated heterocyclic nucleus having 6 to 14 ring atoms and containing 1 to 3 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom. An example of the heterocyclic group includes pyridyl, pyrrolyl, furyl, benzofuryl, thienyl, benzothienyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, puridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl and the like.
Preferred carbocyclic and heterocyclic groups in R1 are (g) a group represented by the formula: 
wherein v is an integer from 0 to 2; R10 and R11 are each independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, optionally substituted phenyl, and C1 to C10 haloalkyl, a is an oxygen atom or a sulfur atom, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; xcex3 is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are an integer from 0 to 5; r is an integer from 0 to 7, and u is an integer from 0 to 4. When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
A more preferable example includes (h) a group represented by the formula: 
wherein R10, R11, xcex1, xcex2, and xcex3 are the same as defined above, and y is independently 0 or 1. When R10 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
The term xe2x80x9cnon-interfering substituentxe2x80x9d in the present specification means a group suitable for substitution of group (a) (e.g., xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d xe2x80x9ccarbocyclic groupxe2x80x9d and xe2x80x9cheterocyclic groupxe2x80x9d) in R1 on tricyclic compound represented by the formula (I). An example of the non-interfering substituents includes C1 to C10 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C7 to C12 aralkyl (such as benzyl and phenethyl), C7 to C12 alkaryl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C10 alkyloxy, C1 to C6 alkyloxy C1 to C6 alkyl (such as methyloxymethyl, ethyloxymethyl, methyloxyethyl, and ethyloxyethyl), C1 to C6 alkyloxy C1 to C6 alkyloxy (such as methyloxymethyloxy and methyloxyethyloxy), C1 to C6 alkylcarbonyl (such as methylcarbonyl and ethylcarbonyl), C1 to C6 alkylcarbonylamino (such as methylcarbonylamino and ethylcarbonylamino), C1 to C6 alkyloxyamino (such as methyloxyamino and ethyloxyamino), C1 to C6 alkyloxyaminocarbonyl (such as methyloxyaminocarbonyl and ethyloxyaminocarbonyl), mono or di C1 to C6 alkylamino (such as methylamino, ethylamino, dimethylamino, and ethylmethylamino), C1 to C10 alkylthio, C1 to C6 alkylthiocarbonyl (such as methylthiocarbonyl and ethylthiocarbonyl), C1 to C6 alkylsulfinyl (such as methylsulfinyl and ethylsulfinyl), C1 to C6 alkylsulfonyl (such as methylsulfonyl and ethylsulfonyl), C2 to C6 haloalkyloxy (such as 2-chloroethyloxy and 2-bromoethyloxy), C1 to C6 haloalkylsulfonyl (such as chloromethylsulfonyl and bromomethylsulfonyl), C1 to C10 haloalkyl, C1 to C6 hydroxyalkyl (such as hydroxymethyl and hydroxyethyl), C1-C6 alkyloxycarbonyl (such as methyloxycarbonyl and ethyloxycarbonyl), xe2x80x94(CH2)zxe2x80x94Oxe2x80x94(C1 to C6 alkyl), benzyloxy, aryloxy (such as phenyloxy), arylthio (such as phenylthio), xe2x80x94CONHSO2R20, formyl, amino, amidino, halogen, carbamyl, carboxyl, carbalkyloxy, xe2x80x94(CH2)zxe2x80x94COOH (such as carboxymethyl, carboxyethyl, and carboxypropyl), cyano, cyanoguanidino, guanidino, hydrazido, hydrazino, hydroxy, hydroxyamino, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, carbocyclic groups, heterocyclic groups and the like, wherein z is an integer from 1 to 8 and R20 is C1 to C6 alkyl or aryl. Preferable are halogens, C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, and C1 to C6 haloalkyl as the xe2x80x9cnon-interfering substituentxe2x80x9d in the R1. More preferable are halogens, C1 to C3 alkyl, C1 to C3 alkyloxy, C1 to C3 alkylthio, and C1 to C3 haloalkyl.
The term xe2x80x9chalogenxe2x80x9d in the present specification means fluorine, chlorine, bromine, and iodine.
The term xe2x80x9ccycloalkylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms. An example of the cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms and at least one double bond(s). An example of the cycloalkenyl includes 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl and the like.
In the present specification, an example of xe2x80x9calkyloxyxe2x80x9d includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy and the like.
In the present specification, an example of xe2x80x9calkylthioxe2x80x9d includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, n-hexylthio and the like.
The term xe2x80x9cacidic groupxe2x80x9d in the present specification means an organic group functioning as a proton donor capable of hydrogen bonding when attached to a tricyclic nucleus through a suitable linking atom (hereinafter defined as xe2x80x9cacid linkerxe2x80x9d). An example of the acidic group includes (k) a group represented by the formula: 
wherein R16 is a hydrogen atom, a metal, or C1 to C10 alkyl; each R17 is independently a hydrogen atom or C1 to C10 alkyl; h is an integer from 1 to 8. Preferable is (l) xe2x80x94COOH, xe2x80x94SO3H, or P(O)(OH)2. More preferable is (m) xe2x80x94COOH. And preferable is also their ester and prodrug.
The term xe2x80x9cacid linkerxe2x80x9d in the present specification means a divalent linking group represented by a symbol xe2x80x94(L2)xe2x80x94, and it functions to join tricyclic nucleus to an xe2x80x9cacidic groupxe2x80x9d in the general relationship. An example of it includes (n) a group represented by the formula: 
wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94(N15)xe2x80x94, or xe2x80x94Sxe2x80x94, and R13 and R14 are each independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or halogens, wherein R15 is a hydrogen atom or C1-C6 alkyl. Preferable are (o) xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94N(R15)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94, or xe2x80x94Oxe2x80x94CH((CH2)2Ph)xe2x80x94 wherein R15 is a hydrogen atom, C1 to C6 alkyl and Ph is phenyl. More preferable is (p) xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94, or xe2x80x94Sxe2x80x94CH2xe2x80x94.
In the present specification, the term xe2x80x9cacid linker lengthxe2x80x9d means the number of atoms (except for hydrogen atoms) in the shortest chain of a linking group xe2x80x94(L2)xe2x80x94 which connects tricyclic nucleus with the xe2x80x9cacidic groupxe2x80x9d. The presence of a carbocyclic ring in xe2x80x94(L2)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene and cyclohexane ring in the acid linker counts as two atoms in culculating the length of xe2x80x94(L2)xe2x80x94. A preferable length is 2 to 3.
The term xe2x80x9chaloalkylxe2x80x9d in the present specification means the aforementioned xe2x80x9calkylxe2x80x9d substituted with the aforementioned xe2x80x9chalogenxe2x80x9d at arbitrary position(s). An example of the haloalkyl includes chloromethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d in the present specification means the aforementioned xe2x80x9calkylxe2x80x9d substituted with hydroxy at arbitrary position(s). An example of the hydroxyalkyl includes hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. In this case, hydroxymethyl is preferable.
In the present specification, the term xe2x80x9chaloalkylxe2x80x9d in xe2x80x9chaloalkyloxyxe2x80x9d is the same as defined above. An example of it includes 2-chloroethyloxy, 2-trifluoroethyloxy, 2-chloroethyloxy and the like.
The term xe2x80x9carylxe2x80x9d in the present specification means a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Particularly, phenyl and 1-naphthyl are preferred.
The term xe2x80x9caralkylxe2x80x9d in the present specification means a group wherein C1 to C8 alkyl is substituted with the above-mentioned xe2x80x9carylxe2x80x9d. Such aryl may have a bond at any substitutable position. An example of it includes benzyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphthylmethyl (such as 1-naphthylmethyl) and the like.
The term xe2x80x9calkyloxycarbonylxe2x80x9d in the present specification means C1-C6 alkyloxycarbonyl. An example of the alkyloxycarbonyl includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl and the like.
The term xe2x80x9cacylxe2x80x9d in the present specification means C1-C6 alkylcarbonyl or arylcarbonyl opptionally substituted with a halogen and the like. An example of the acyl includes acetyl, trifluoroacetyl, propionyl, benzoyl and the like.
A group of preferable substituents as the R1 to R3 of the compound represented by the formula (I) will be shown in items (A) to (O). Preferable are hydrogen atoms as the R4, R18, R19, R20, R21, R22, R23, R25, R26, and R27. Item (f) to (p) are the same groups as described above.
As the R1, (A):xe2x80x94(L1)xe2x80x94R5, (B):xe2x80x94(CH2)1-2-(f), (C):xe2x80x94(CH2)1-2-(g), (D):xe2x80x94(CH2)1-2-(h) are preferred.
As the R2, (E): CONH2 or CONHNH2, and (F): CONH2 are preferred.
As the R3, (G):-(n)-(k), (H):-(n)-(l), (I):-(n)-(m), (J):-(o)-(k), (K):-(o)-(l), (L):-(o)-(m), (M):-(p)-(k), (N):-(p)-(l), and (O):-(p)-(m) are preferred.
A preferred group of compounds represented by the formula (I) is shown below.
(R1,R2,R3)=(A,E,G), (A,E,H), (A,E,I), (A,E,J), (A,E,K), (A,E,L), (A,E,M), (A,E,N), (A,E,O), (A,F,G), (A,F,H), (A,F,I), (A,F,J), (A,F,K), (A,F,L), (A,F,M), (A,F,N), (A,F,O), (B,E,G), (B,E,H), (B,E,I), (B,E,J), (B,E,K), (B,E,L), (B,E,M), (B,E,N), (B,E,O), (B,F,G), (B,F,H), (B,F,I), (B,F,J), (B,F,K), (B,F,L), ((B,F,M), (B,F,N), (B,F,O), (C,E,G), (C,E,H), (C,E,I), (C,E,J), (C,E,K), (C,E,L), (C,E,M), (C,E,N), (C,E,O), (C,F,G), (C,F,H), (C,F,I), (C,F,J), (C,F,K), (C,F,L), (C,F,M), (C,F,N), (C,F,O), (D,E,G), (D,E,H), (D,E,I), (D,E,J), (D,E,K), (D,E,L), (D,E,M), (D,E,N), (D,E,O), (D,F,G), (D,F,H), (D,F,I), (D,F,J), (D,F,K), (D,F,L), (D,F,M), (D,F,N), and (D,F,O).
For each group as the R4, a hydrogen atom, C1 to C3 alkyl and aryl are preferable.
The compounds of the invention represented by the formula (I) can be synthesized in accordance with well-known method described in chemical journals. The compounds of the invention represented by the formula (I) can also be synthesized in accordance with the following methods A and method B. Although representative methods are exemplified, enlarged rings can also be synthesized in a similar manner.
(Method A) 
wherein R1, R4, and R24 are as defined above, R28, R29 and R31 is C1 to C3 alkyl, R36 is a protecting group of hydroxy (e.g., tetrahydropyranyl or the like), R30 is a hydrogen atom or C1 to C3 alkyl, Hal are each independently a halogen.
(Process 1)
To a solution of the compound (V) in a solvent such as dimethylformamide or the like are added an alkyl halide derivative and a base (e.g. potassium carbonate, potassium t-butoxide, sodium hydride or the like), and the mixture is reacted at room temperaturre to 180xc2x0 C., preferably 20 to 150xc2x0 C. for 3 to 80 h, preferably 5 to 70 h to give the compound (VI).
(Process 2)
To a solution of the compound (VI) in a solvent such as dimethylsulfoxide or the like is added a reagent such as potassium acetate, sodium acetate or the like, and the mixture is reacted at 20xc2x0 C. to 200xc2x0 C., preferably 100xc2x0 C. to 180xc2x0 C. for 3 to 17 h to obtain the compound (VII).
(Process 3)
To a solution of a Grignard reagent (R1MgHal, Hal is a halogen) or R1Li in a solvent such as ether, tetrahydrofuran, or dimethoxyethane is added a solution of the compound (VII) in a solvent such as ether, tetrahydrofuran, or dimethoxyethane at xe2x88x9220xc2x0 C. to 30xc2x0 C., and the mixture is reacted at 0xc2x0 C. to 70xc2x0 C., preferably 20 C to 60xc2x0 C. for 1 to 48 h, preferably 2 to 24 h to obtain the compound (VIII).
(Process 4)
To a solution of the compound (VIII) in a solvent such as ethanol, methanol, dioxane, tetrahydrofuran or the like are added N-aminophthalimide and an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid or the like, and the mixture is reacted at 20xc2x0 C. to 120xc2x0 C., preferably 50xc2x0 C. to 100xc2x0 C. for 6 min to 2 h, preferably 10 min to 1 h to yield the compound (IX).
(Process 5)
The present process includes the deprotection of a phthalimide group of the compound (IX). This can be carried out by usual deprotection (to see Protective Groups in Organic Synthesis, Theodora W Green (John Wilkey and Sons)). For example, to a solution of the compound (IX) in an alcoholic solvent such as ethanol or the like is added hydrazine, and the mixture is reacted at 50xc2x0 C. to 100xc2x0 C., for 0.5 to 3 h to yield the amino compound (X).
(Process 6)
To a solution of the compound (X) in a solvent such as chloroform, dichloroethane, tetrahydrofuran, toluene or the like are added xcex2-ketoester (e.g., acetoacetic acid methyl ester) and an acid catalyst (e.g., p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid or the like), and the mixture is reacted at 20xc2x0 C. to 150xc2x0 C., preferably 30xc2x0 C. to 100xc2x0 C. for 1 to 20 h, preferably 3 to 16 h to yield the compound (XI). Water which is yielded in the reaction is dehydrated with a Dean-stark filled with molecular sieves 4A.
(Process 7)
To a solution of the compound (XI) in a solvent such as tetrahydrofuran, dimethylformamide or the like are added a base such as potassium carbonate, sodium hydride or the like and an alkyl halide derivative, and the mixture is reacted at 0xc2x0 C. to 100xc2x0 C., preferably 20 to 40xc2x0 C. for 1 to 15 h to obtain the compound (XII).
(Process 8)
The present process includes the conversion of a hydroxy group to a halogen. To a solution of the compound (XII) in a solvent such as dichloromethane or the like are added reagents such as triphenylphosphine and carbon tetrachloride, N-bromosuccimide or the like, and the mixture is reacted at 0xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 1 to 10 h, preferably for 1 to 5 h to obtain the compound (XIII).
(Process 9)
The present process includes the introduction of a substituent at 5-position. To a solution of the compound (XIII) in a solvent such as dichloromethane or tetrahydrofuran are added Halxe2x80x94C(xe2x95x90X)xe2x80x94C(xe2x95x90X)xe2x80x94Hal (Hal are halogen) (e.g., oxalyl chloride) and a base such as N-methylmorpholine, triethylamine or the like, and the mixture is stirred at xe2x88x9220xc2x0 C. to 70xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 10 min to 10 h, preferably, 10 min to 2 h. The reaction mixture is poured into a cold aqueous ammonium and the resulting reaction mixture is subjected to a usual work-up, and then the compound (XIV) can be obtained.
(Process 10)
The present process includes the preparation of the phosphonium salt. A mixture of the compound (XIV) and triphenylphosphine in a solvent such as acetonitrile, toluene or the like is reacted at 60xc2x0 C. to 150xc2x0 C., preferably 80xc2x0 C. to 120xc2x0 C. for 5 to 100 h, preferably 10 to 70 h to obtain the compound (XV).
(Process 11)
The present process is the one for constructing a ring by Wittig reaction. To a solution of the compound (XV) in a solvent such as dichloromethane, acetonitrile, tetrahydrofuran or the like is added a base such as 1,8-dizabicyclo[6.4.0]-7-undecene (DBU), potassium t-butoxide or the like, and the mixture is reacted at 20xc2x0 C. to 120xc2x0 C., preferably 30xc2x0 C. to 100xc2x0 C. for 3 to 24 h, preferably 5 to 10 h to obtain the compound (XVI).
(Process 12)
The present process includes hydrolysis. To a solution of the compound (XVI) in a solvent such as methanol, tetrahydrofuran or the like is added a base such as sodium hydroxide or the like, and the mixture is reacted at 0xc2x0 C. to 40xc2x0 C., preferably 10xc2x0 C. to 30xc2x0 C. for 0.5 to 6 h, preferably for 0.5 to 2 h, to obtain the compound (XVII).
(Method B) 
wherein R1, R24, R25, R30, R31, and Hal are defined above. R32 and R33 C1 to C3 alkyl, R34 is a precursor of R1, R35 C1-C3 alkyl, optionally substituted aryl (e.g., tolyl or the like), R37 is acyl (e.g., acetyl, benzoyl or the like), Ms mesyl;
(Process 1)
The present process is the one for constructing pyrrolo[1,2-a]pyrazine ring. A mixture of the compound (XVIII) and Halxe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94(CH2)mxe2x80x94CO2R33 is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 50xc2x0 C. to 70xc2x0 C. for 3 to 36 preferably 12 to 24 h, to obtain a quaternary salt. The resulting quaternary salt is dissolved in a solvent such as 1,2-dichloroethane, acetonitrile or the like, a base such as 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU), triethylamine or the like is added to the solution, and the mixture is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 60xc2x0 C. to 80xc2x0 C. for 1 to 10 hours, preferably 1 to 5 h. When the resulting product is subjected to a usual work-up, the compound (XIX) can be obtained.
(Process 2)
The present process is the one for introducing a substituent to 6-position of pyrrolo[1,2-a]pyrazine, and it may be carried out by Friedel-Crafts reaction. The compound (XIX) is dissolved in a solvent such as dichloromethane, chlorobenzene or the like, R34COHal and Lewis acid (e.g., AlCl3, SbF5, BF3 and the like) are added gradually to the solution at xe2x88x9278xc2x0 C. to 10xc2x0 C., preferably xe2x88x9220xc2x0 C. to 0xc2x0 C., and the resulting mixture is stirred at xe2x88x9210xc2x0 C. to 10xc2x0 C., preferably 0xc2x0 C. to 10xc2x0 C. for 30 min to 5 h, preferably 1 h to 3 h. When the resulting product is subjected to a usual work-up, the compound (XX) can be obtained.
(Process 3)
The present process is the one for reduction of the ester group and the ketone group to the alcohol groups. To a solution of the compound (XX) in a solvent such as ether, tetrahydrofuran or the like is reacted with a reductant such as lithium aluminum hydride, lithium borohydride or the like at 0xc2x0 C. to 80xc2x0 C., preferably 10xc2x0 C. to 40xc2x0 C. for 30 min to 10 h, preferably for 1 h to 5 h, to obtain the compound (XXI).
(Process 4)
The present process is the one for reductive elimination of the hydroxy group and transformation the same into methylene. Lewis acid (for example, AlCl3 and the like) is dissolved in a solvent such as dichloromethane, tetrahydrofuran or the like, a reducing agent such as boron-t-butylamine complex, sodium borohydride or the like is added to the solution at xe2x88x9220xc2x0 C. to 10xc2x0 C., preferably under ice-cooling, and the resulting mixture is stirred for 5 to 30 minutes, preferably 10 to 20 minutes. The compound (XXI) is added to the reaction mixture at xe2x88x9220xc2x0 C. to 10xc2x0 C., preferably under ice-cooling, the resulting mixture is reacted at 15xc2x0 C. to 40xc2x0 C., preferably 20xc2x0 C. to 30xc2x0 C. for 30 min to 5 h, preferably 1 to 3 h to obtain the compound (XXII).
(Process 5)
The present process is the one for transforming the alkyloxy group into ketone. An acid such as concentrated hydrochloric acid or the like is added to the compound (XXII), and the mixture is stirred at 80xc2x0 C. to 150xc2x0 C., preferably 100xc2x0 C. to 120xc2x0 C. for 1 to 5 h, preferably 1 to 3 h. When the resulting product is subjected to a usual work-up, the compound (XXIII) can be obtained.
(Process 6)
The present process is the one for protecting the hydroxy group with a acetyl group. A solution of the compound (XXIII) in pyridine is reacted with acetic anhydride at 0xc2x0 C. to 50xc2x0 C., preferably 20xc2x0 C. to 40xc2x0 C. for 1 to 10 h, preferably 3 to 8 h to give the compound (XXIV).
(Process 7)
The present process is the one for transforming the ketone at 1-position into a halogen. A halogenating agent such as phosphorus oxychloride, phenylphosphonic dichloride or the like is added to the compound (XXIV), and the mixture is stirred at 60xc2x0 C. to 150xc2x0 C., preferably 80xc2x0 C. to 110xc2x0 C. for 10 min to 3 h, preferably 30 min to 1 h. When the resulting product is subjected to an ordinary work-up, the compound (XXV) can be obtained.
(Process 8)
The present process is the one for converting the halogen at 1-position into a sulfonyl group. To a solution of the compound (XXV) in ethanol is added R36SO2Na, and the mixture is refluxed for 10 to 50 h, preferably 24 to 36 h to obtain the compound (XXVI).
(Process 9)
The present process is the one for transforming the sulfonyl group at 1-position into an alkyloxy group. A suspension of HOCH(R30)CO2R31 and a reagent such as sodium hydride, potassium t-butoxide or the like in a solvent such as tetrahydrofuran or the like is stirred at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 15 min to 2 h, preferably 30 min to 1 h. To the mixture is added the compound (XXVI), and the reaction mixture is reacted at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 15 min to 5 h, preferably 30 min to 2 h to yield the compound (XXVII).
(Process 10)
The present process may be carried out in accordance with the same manner as that of the method Axe2x80x94process 9.
(Process 11)
The present process is the one for deprotecting the acetyl group. To a solution of the compound (XXVIII) in a solvent mixed with tetrahydrofuran and methanol is added hydrochloric acid and the mixture is stirred at 0xc2x0 C. to 50xc2x0 C., preferably 20xc2x0 C. to 30xc2x0 C. for 1 to 10 h, preferably 3 to 8 h to obtain the compound (XXIX).
(Process 12)
The present process is the one for converting the hydroxy group into xe2x80x94OSO2Me. A solution of the compound (XXIX) in a solvent such as dichloromethane, tetrahydrofuran or the like is reacted in the presence of a base such as triethylamine, pyridine or the like with methanesulfonyl chloride at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 10 min to 5 h, preferably 30 min to 2 h to obtain the compound (XXX).
(Process 13)
The present process is the one for transformation of the xe2x80x94OSO2Me group into a halogen. A solution of the compound (XXX) in a solvent such as acetonitrile, acetone, dimethylformamide or the like is reacted with a reagent such as lithium bromide, lithium chloride or the like at 0xc2x0 C. to 100xc2x0 C., preferably 30xc2x0 C. to 60xc2x0 C. for 1 to 10 h, preferably 1 to 5 h to obtain the compound (XXXI).
(Process 14)
The present process may be carried out in accordance with the same manner as that of the method Axe2x80x94process 10.
(Process 15)
The present process may be carried out in accordance with the same manner as that of the method Axe2x80x94process 11.
(Process 16)
The present process may be carried out in accordance with the same manner as that of the method Axe2x80x94process 12.
Where a compound of the present invention has an acidic or basic functional group, a variety of salts having higher water solubility and more physiologically suitable properties than those of the original compound can be formed. An example of typical pharmaceutically acceptable salts includes salts with alkali metal and alkaline earth metal such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like, but it is to be noted that such pharmaceutically acceptable salts are not limited thereto. A salt is easily manufactured from a free acid by either treating an acid in a solution with a base, or allowing an acid to be in contact with an ion exchange resin. Additional salts of the compounds according to the present invention with relatively non-toxic inorganic bases and organic bases, for example, amine cation, ammonium, and quaternary ammonium derived from nitrogenous bases having a basicity sufficient for forming a salt of the compounds of the present invention are included in the definition of xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d. (e.g., S. M. Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66, 1-19 (1977)) Furthermore, basic groups of a compound according to the present invention are reacted with a suitable organic or inorganic acid to form salts such as acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartarate, borates, bromides, camcyrates, carbonates, chlorides, clubranates, citrates, edetates, edicirates, estrates, ethylates, fluorides, fumarates, gluseptates, gluconates, glutamates, glycolialsanyrates, hexylresorcinates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, malates, malseates, manderates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napcylates, nitrates, oleates, oxarates, palmitates, pantothenates, phosphates, polygalacturonates, salicirates, stearates, subacetates, sucinates, tanates, tartrates, tosylates, trifluoroacetates, trifluoromethanesulfonates, valerates and the like. In case of forming a hydrate, a questioned compound may be coordinated with a suitable number of water molecules.
In the case where a compound of the present invention has one or more of chiral center(s), it may exist as an optically active member. Likewise, in the case where a compound contains alkenyl or alkenylene, there is a possibility of cis- and trans-isomers. Mixtures of R- and S-isomers as well as of cis- and trans-isomers, and mixtures of R- and S-isomers containing racemic mixture are included in the scope of the present invention. Asymmetric carbon atom may exist also in a substituent such as alkyl group. All such isomers are included in the present invention together with these mixtures. In the case where a specified streoisomer is desired, either it is manufactured by applying a manner which has been well known by those skilled in the art wherein a starting material having an asymmetrical center which has been previously separated is subjected to stereospecific reaction to the starting material, or it is manufactured by preparing a mixture of stereoiromers, and thereafter separating the mixture in accordance with a well-known manner.
Prodrug is a derivative of the compound having a group which can be decomposed chemically or metabolically, and such prodrug is a compound according to the present invention which becomes pharmaceutically active by means of solvolysis or by placing the compound in vivo under a physiological condition. Although a derivative of the compounds according to the present invention exhibits activity in both forms of acid derivative and basic derivative, acid derivative is more advantageous in solubility, tissue affinity, and release control in mammal organism (Bungard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam, 1985). For instance, prodrugs each containing an acid derivative such as an ester which is prepared by reacting a basal acid compound with a suitable alcohol, or an amide which is prepared by reacting a basal acid compound with a suitable amine are well known by those skilled in the art. Simple aliphatic or aromatic esters derived from acid groups contained in the compounds according to the present invention are preferable prodrugs. More preferable is C1-C6 alkyl ester of acidic group (e.g., methyl ester, ethyl ester). Double ester such as (acyloxy)alkyl ester or ((alkyloxycarbonyl)oxy)alkyl ester type prodrugs may be optionally manufactured.
The term xe2x80x9cinhibitxe2x80x9d means that release of fatty acid started by sPLA2 decreases significantly by the compounds of the present invention from viewpoint of prevention and treatment of disease. The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means that carriers, diluents, or additives are compatible with other ingredients in a formulation and are not harmful for recipients.
The compounds of the present invention exhibit sPLA2 inhibiting activity as per the description of the experimental examples which will be described hereinafter. Accordingly, when a curatively effective amount of the compounds represented by the formulae (I), (II), and (III), the prodrug derivatives thereof, or their pharmaceutically acceptable salts, or their hydrate is administered to any of mammals (including human being), it functions effectively as a curative medicine for diseases of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral. infarction, inflammatory colitis, psoriasis, cardiac failure, cardiac infarction.
The compounds of the present invention may be administered to a patient through a variety of routes including oral, aerosol, rectal, percutaneous, subcutaneous, intravenous, intramuscular, and nasal routes. A formulation according to the present invention may be manufactured by combining (for example, admixing) a curatively effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The formulation of the present invention may be manufactured with the use of well-known and easily available ingredients in accordance with a known method.
In case of manufacturing a composition according to the present invention, either active ingredients are admixed with a carrier, or they are diluted with a carrier, or they are contained in a carrier in the form of capsule, sacheier, paper, or another container. In case of functioning a carrier as a diluent, the carrier is a solid, semi-solid, or liquid material which functions as a medium. Accordingly, a formulation according to the present invention may be produced in the form of tablet, pill, powder medicine, intraoral medicine, elixir agent, suspending agent, emulsifier, dissolving agent, syrup agent, aerosol agent (solid in liquid medium), and ointment. Such a formulation may contain up to 10% of an active compound. It is preferred to prepare a compound according to the present invention prior to administration.
Any suitable carrier which has been well known by those skilled in the art may be used for the formulation. In such formulation, a carrier is in the form of solid, liquid, or a mixture of solid and liquid. For instance, a compound of the present invention is dissolved into 4% dextrose/0.5% sodium citrate aqueous solution so as to be 2 mg/ml concentration for intravenous injection. Solid formulation includes powder, tablet, and capsule. Solid carrier consists of one or more of material(s) for serving also as fragrant, lubricant, dissolving agent, suspension, binder, tablet disintegrator, capsule. A tablet for oral administration contains a suitable excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and the like together with a disintegrator such as corn starch, alginic acid and the like and/or a binder such as gelatin, acacia and the like, and a lubricant such as magnesium stearate, stearic acid, talc and the like.
In a powder medicine, a carrier is a finely pulverized solid which is blended with finely pulverized active ingredients. In a tablet, active ingredients are admixed with a carrier having required binding power in a suitable ratio, and it is solidified in a desired shape and size. Powder medicine and tablet contain about 1 to about 99% by weight of the active ingredients being novel compounds according to the present invention. An example of suitable solid carriers includes magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methyl cellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter.
An axenic liquid formulation contains suspending agent, emulsifier, syrup agent, and elixir agent. Active ingredients may be dissolved or suspended into a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent, a mixture thereof and the like. Active ingredients may be dissolved frequently into a suitable organic solvent such as propylene glycol aqueous solution. When finely pulverized active ingredients are dispersed into aqueous starch, sodium carboxylmethylcellulose solution, or suitable oil, the other compositions can be prepared.
The dosage varies with the conditions of the disease, administration route, age and body weight of patient. In the case of oral administration, the dosage can generally be between 0.01 to 50 mg/kg/day for adult.
The following examples are provided to further illustrate the present invention and are not to be constructed as limiting the scope thereof.
Abbreviations described below are used in the following examples.
Me: methyl
Et: ethyl
Hex: hexyl
Ph: phenyl
Bn: benzyl
Tol: tolyl
Ac: acetyl
Ms: mesyl
DBU: 1,8-diazabicyclo[5.4.0]-7-undecene